CN101669935A - Drug combination containing prunetin and application thereof in drugs - Google Patents
Drug combination containing prunetin and application thereof in drugs Download PDFInfo
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- CN101669935A CN101669935A CN200910206250A CN200910206250A CN101669935A CN 101669935 A CN101669935 A CN 101669935A CN 200910206250 A CN200910206250 A CN 200910206250A CN 200910206250 A CN200910206250 A CN 200910206250A CN 101669935 A CN101669935 A CN 101669935A
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- pharmaceutical composition
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- prunusetin
- pratensein
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Abstract
The invention relates to a drug combination containing pratensein and/or prunetin, which has the effects of preventing and treating cardiovascular systems, osteoporosis and the like via the effects ofselective estrogen receptor modulators widely distributed in the bodies. The combination can be used for preparing the drugs for treating cancers and lead compounds. The combination can be orally taken by the patients or be applied to the patients who need the treatment by nasal inhalation or in an external rectal, parenteral or local manner. The daily dose of the combination is 1mg-4mg/kg and the combination can be applied once or more times. The combination can be prepared into solid preparations, liquid preparations, creams, ointments, patches, spraying agents, subcutaneous implants and the like, and can be especially prepared into sustained release tablets, coated tablets and the like having effects on intestinal canals.
Description
The application is denomination of invention dividing an application for " a kind of pharmaceutical composition that contains pratensein, prunusetin. and in pharmaceutically application ", application number 200510031097.3, the patent application in October 25 2005 applying date.
Technical field
The present invention relates to medical composition and its use, be specifically related to contain the pharmaceutical composition of pratensein (Pratensein), prunusetin. (Prunetin) and in pharmaceutically application.
Background technology
The osajin composition extensively is present in the plant, has multiple biological activity, as effects such as anticancer, blood fat reducing, the effect of plant estrogen sample, human body immunity improving power, the correlational study of relevant flavones ingredient is paid attention to by Chinese scholars always and is deepened continuously.
Herba Trifolii Pratentis (Trifolium pretense L.) has another name called Herba Trifolii Pratentis, red clover etc., be used as herbage more, contain multiple flavone and osajin component cpd in the herb, modern pharmacological research proves, Herba Trifolii Pratentis has significant biological activity, and the activity of having reported has:
1, estrogen sample effect: contain multiple osajin composition in this plant and have the effect of estrogen sample, as biochanin (biochanin) A and B (being formononetin formononetin), genistein (genistein), big legumin (daidzein) etc., but the estrogen-like effects of above-mentioned isoflavone all a little less than, also have research to think the most weak or non-activity of biochanin B effect certainly.
2, antitumaous effect: have report to claim this product water extract to give rats gavaged or injection, can suppress sarcoma S
45Growth; Wherein contained genistein has cytotoxic activity to human nasopharyngeal carcinoma KB cell.
3, effect for reducing blood fat: report shows that genistein can reduce the effect of triglyceride and cholesterol in the serum, and Biochanin A also can suppress serum cholesterol and raises, and big legumin also shows tangible effect for reducing fat.
4, other effect: have bibliographical information this product that the resisting pathogenic microbes effect is arranged, wherein contained trifolirhizin has the antifungal effect.
So far; the Herba Trifolii Pratentis total flavones of report or Herba Trifolii Pratentis extract are many to be main constituent with Biochanin A and B; or double a small amount of genistein, the big legumin be with; pratensein wherein, the content of prunusetin. are very little; generally do not list the content detection scope in, their chemical structural formula is:
R
1 R
2 R
3 R
4
Biochanin A (biochanin) Me OH H H
Biochanin B (formononetin) Me H H H
Big legumin (daidzein) H H H H
Genistein (genistein) H OH H H
Pratensein (pratensein) Me OH H H
Prunusetin. (prunetin) H OH H Me
Up to the present, yet there are no both at home and abroad pratensein, prunusetin. or its glycoside as the research report of selective estrogen receptor modulators and the report of the medical applications aspect of being correlated with.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of pharmaceutical composition that contains pratensein and/or prunusetin., by the selective estrogen receptor modulators effect, has prevention and effects such as treatment cardiovascular system, osteoporosis and cancer.
Pratensein of the present invention and/or prunusetin. are measured estrogenic activity with the E-SCREEN method of classics, demonstrate the propagation that the two all can promote the MCF-7 cell, have estrogen-like effects, and activity is 10 of a medicine estradiol
-5-10
-3
Pratensein of the present invention and/or prunusetin. are brought into play selectively acting to some estrogen responsiveness tissue in cardiovascular system is unified skeleton.In vitro tests confirms that also the two all can promote osteoblastic propagation significantly, and can significantly increase cellular matrix calcium and mineralising tuberosity calcium.Show that having prevention and treatment cardiovascular system diseases and osteoporosis aspect can play a role.
Zoopery of the present invention finds that also the toxicity of pratensein or prunusetin. is very low, and the behavior of animal does not have any significant change yet during heavy dose of the use.
It is active component that pharmaceutical composition of the present invention contains above-mentioned general formula (1) pratensein, the prunusetin. for the treatment of effective dose, and contains one or more pharmaceutically acceptable carriers.
Pratensein of the present invention and/or prunusetin. and pharmaceutical composition can be used for preparing the medicine of treatment cancer, menopausal osteoporosis, cardiovascular and cerebrovascular disease and lead compound.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine, for example: diluent, excipient etc.Its dosage form comprises various solid dosage formss and liquid dosage form.Can also in compositions, add other adjuvant and flavouring agent, sweeting agent etc. in addition.
Pratensein of the present invention, prunusetin. can pharmaceutical composition form by oral, snuffing is gone into, the mode of rectum or parenteral, local application is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, powder, granule, capsule etc., make liquid preparation such as water or oiliness suspending agent etc. or other liquid preparation such as syrup etc.; When being used for parenteral, can be made into solution, water or the oiliness suspending agent etc. of injection.During topical, can be made into cream, ointment, patch, spray, subcutaneous implant etc.Preferred form is tablet, slow releasing tablet, coated tablet, capsule, nasal spray, subcutaneous implant, particularly preferably in the preparation of the specific part slow release of intestinal.
The various dosage forms of pharmaceutical composition of the present invention can be according to the production method preparation of pharmaceutical field routine; pratensein and/or prunusetin. active ingredient are mixed with one or more carriers, select different way of administration to be made into the required dosage forms of clinical practice according to different indications.
The active ingredient of pharmaceutical composition of the present invention is a pratensein, and prunusetin. preferably contains the active component that weight ratio is 0.1%-99.5%, most preferably contains the active component that weight ratio is 0.5%-95%.
The amount of application of active ingredient of the present invention can be according to adjustment such as the type of route of administration, patient's age, body weight, the disease of being treated and the orders of severity, and its, dosage was 1mg-4mg/kg every day, can use by one or many.
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Embodiment 1
The estrogenic activity of pratensein (pratensein), prunusetin. (prunetin)
This experiment is biological test carrier with MCF-7 estrogen-dependent breast cancer cell, adopts classical E-SCREEN method to measure its estrogenic activity.
DMSO solvent control group (feminine gender), 1nM estradiol matched group (positive), pratensein group (1uM, 10uM), prunusetin. group (1uM, 10uM) are established in this experiment.
The result shows: pratensein, prunusetin. can promote the propagation of MCF-7 cell significantly, have estrogen-like effects, but its activity only is 10 of an estradiol
-5-10
-3
Embodiment 2
Pratensein (pratensein), prunusetin. (prunetin) and the interactional molecular simulation of estrogen receptor
Adopt the area of computer aided drug design method, with estrogen receptor (ER β, ER α) as the target model, with the method acquisition pratensein of molecular mechanics optimization and the activity conformation of prunetin molecule, with the interaction between molecular docking program calculating receptor and aglucon.
The result shows: pratensein and prunetin all can enter the binding cavity of estrogen receptor, the result also point out the two with the adhesion of ER β than with the strong 7-10 of adhesion of ER α doubly.In addition, some position is substituted on the molecule, and its activity is had certain influence.
Because there are the difference on the tissue distribution in human body ER β and ER α, ER β mainly is present in brain, skeleton, bladder and blood vessel epithelial tissue, and prompting pratensein and prunetin may bring into play selectively acting to some and ER α estrogen responsiveness tissue in cardiovascular system is unified skeleton.
Embodiment 3
Pratensein (pratensein), prunusetin. (prunetin) influence cultured osteoblasts in vitro
Get newborn 1-3 days SD rat skulls and be separated into osteocyte with enzyme digestion, third generation cell is observed the influence to the increment of In vitro culture osteoblast, cellular matrix calcium and mineralising tuberosity calcium of pratensein, prunusetin. through mtt assay, methyl thymol blue (MTB) colorimetry.
The result shows: pratensein, prunusetin. 0.1-10umol/L concentration all can promote osteoblastic proliferation significantly, and can significantly increase cellular matrix calcium and mineralising tuberosity calcium.Concrete outcome sees the following form:
* P＜0.05, * * P＜0.01 and control are relatively;
△P＜0.05,
△ △Compare with NaF P＜0.01
Embodiment 4
Pratensein (pratensein); application pratensein and prunetin and the estrogen receptor interactional molecular simulation results suggest of prunusetin. (prunetin) in field of medicaments; pratensein; prunetin all very likely is a selective estrogen receptor modulators; in conjunction with to the existing achievement in research of selective estrogen receptor modulators; therefore the pratensein and the prunetin utmost point are hopeful exploitation becomes prevention or the relevant medicine with osteoporosis of treatment; prevention or treatment and related to cancer medicine; prevention or treatment and the relevant medicine of relevant disease in menopause; prevention or treatment and diseases of cardiovascular and cerebrovascular systems; protection cardiovascular function medicine, and be used for clinical with various dosage forms uses or various route of administration.
Embodiment 5
The compositions of pratensein, prunusetin. (1: 1) (sample I) is to the influence of ovariectomized rat
With the anesthesia of 30mg/kg pentobarbital sodium intraperitoneal administration, the rat preserved skin is extractd the both sides ovary, and the postoperative recuperation began administration after 9 days.Rat is divided into four groups, normal group, model group, sample I 100mg/kg group, estrogen 50 micrograms/kg group, administration every day.Continue 30 days.
Administration rose on the 20th, and rat vaginal smear every day 10 days is observed physiological period.Draw the normal saline solution of 50 microlitres 0.9% with the liquid-transfering gun of 200 microlitres, inject vagina, resorption irrigating solution, the even smear of slide.Dry back Switzerland dye liquor, the dyeing of Giemsa dye liquor, carry out differential counting under 400 times of ultramicroscope.After the administration 30 days, get serum, on the animal automatic clinical chemistry analyzer, measure serum triglycerides, T-CHOL.Measure rat blood serum estrogen, progestogen content.
Sample I is to the influence of ovariectomized rat serum triglycerides, T-CHOL
Discover that medicine has the trend of triglyceride reducing and T-CHOL.
Preliminary experiment is the result show, sample I has certain effect to the uterus weight of ovariectomized rat, the variation of vagina physiological period, serum triglycerides, T-CHOL etc.
Annotate: what sample I represented is the compositions of pratensein, prunusetin. (1: 1)
Embodiment 6
Sample I is to the preventive effect of rats with osteoporosis due to the retinoic acid.
Rat is divided into 6 groups at random, the normal control group, model control group, sample I is low, in, high dose group, positive controls, except that the normal control group, each organizes all oral retinoic acid 70mg/kg of rat, dose 1ml/100g rat, every day 1 time, continuous 14 days, respectively organize the oral successively following sample of rat, normal control group simultaneously every day, retinoic acid group is coordinative solvent 10ml/kg, sample I low dose group 4mg/kg, middle dosage group 12mg/kg, high dose group 36mg/kg, positive drug ethoxy Alendronate 50mg/kg, dose is the 1ml/100g rat, every day 1 time, continuous 28 days, weigh weekly therebetween 1 time, adjust the administration consumption with body weight.
Administration finishes, and gets blood system from serum, presses kit method and surveys S-Ca, S-P content, gets rat bilateral femur, in the scanning of X line borne densitometers, measures bone density (g/cm
2), claim bone heavy (W), survey bone long (L), bone diameter (D) calculates bone lines of expression density (W/L), apparent surface density (W/LD), dried one hour for 110 ℃ then, place interior 200,400,600,800 ℃ of each ashing of muffle furnace 2 hours again, after ashing finishes cooling, claim ash to weigh (Washg), extract the back with 6NHCl and survey bone ash Ca, bone ash P content, the gram numerical table that contains Ca or P with the 100g bone ash shows.
Opposite side femoral head 3%HNO
3Make paraffin section after the decalcification, HE dyeing, microscopically is surveyed the bone trabecula width.Above result all compares with administration group and model group, and model group and normal control group are relatively.
Each treated animal body weight no significant difference (P＞0.05) in the experiment same day and the 1st week, 2,4 all retinoic acid group weight ratio normal control groups lose weight (P＜0.01, P＜0.05) after the administration, but each treated animal body weight all obviously increases after the medication, wherein low dose group (4mg/kg) has weight increase but no statistical significance, and the middle and high dosage group of sample I sample I (12mg/kg, 36mg/kg) and the body weight in ethoxy Alendronate group the 2nd, 4 weeks of rat all increase (P＜0.05) than model group, and each dosage group compares no significant difference mutually.
Model group rat femur bone density is than normal control group low (P＜0.01), serum Ca content is also than model group low (P＜0.05), the serum paraoxonase changes of contents is little, but medication group rat femur density all increases (P＜0.05, P＜0.01) than model group, the content of serum calcium and phosphorus all raises than model group, but the middle and high dosage group of sample I no significant difference.The rat femur bone density of positive drug ethoxy Alendronate and serum calcium serum paraoxonase content also have evident difference (P＜0.05, P＜0.01) than model group.
Sample I is as follows to the bone index influence of Induced by Retinoic Acid rats with osteoporosis preventive effect:
Compare with matched group, the W of model group, L, d, W/L, W/Ld all obviously descend, with respect to all obviously raisings of W, W/Ld of middle and high dosage group of model group sample I and ethoxy Alendronate group
With matched group relatively, the bone ash of model group reaches heavily that bone Ca and bone P content all reduce in the ash, but the middle and high dosage group of sample I and ethoxy Alendronate group bone ash weight, bone Ca, all increases relatively of bone P content after the medication
Embodiment 7
Method for preparing tablet thereof: active component, lactose and starch mix, and water is evenly moistening, the mixture after moistening are sieved and drying, after sieve, add magnesium stearate, then with the mixture tabletting, and every heavy 250mg, active component content 10mg.
Embodiment 8
Capsule preparation method thereof: active component is mixed with auxiliary agent, sieve, uniform mixing in suitable containers, the mixture that the obtains hard gelatin capsule of packing into, the heavy 200mg of each capsule, active component content 50mg.
Embodiment 9
The injection preparation method: active component and sodium chloride 9mg are dissolved in an amount of water for injection, filter gained solution, in the peace of under aseptic condition, packing into the bottle, active component content 10mg.
Embodiment 10
Nasal spray preparation method: active component 1mg, sodium chloride 8mg, EDTA1mg, sodium phosphate buffer (pH6-7) 10mg, Spheron MD 30/70 10mg, heavy distilled water adds to 2ml, stir a kind of composition of each adding in the heavy distilled water of proper volume down, after adding water to 2ml., this solution is filtered on sterilizing filter, separate in the bottle of packing into and according to suitable dosage.
Claims (9)
1, the application of prunusetin. in preparation prevention or treatment osteoporosis, diseases of cardiovascular and cerebrovascular systems or cancer drug.
2, application as claimed in claim 1 is characterized in that: described osteoporosis is a menopausal osteoporosis disease.
3, the application of prunusetin. in preparation selective estrogen receptor modulators or lead compound.
4, a kind of pharmaceutical composition is characterized in that this pharmaceutical composition comprises the prunusetin. as active component.
5, pharmaceutical composition as claimed in claim 4 is characterized in that: described pharmaceutical composition is solid dosage forms or liquid dosage form.
6, pharmaceutical composition as claimed in claim 4 is characterized in that: described pharmaceutical composition be oral, snuffing is gone into, rectum or parenteral, or the pharmaceutical dosage form of local application.
7, pharmaceutical composition as claimed in claim 6 is characterized in that:
Described oral pharmaceutical dosage form is tablet, powder, granule, capsule, aqueous suspension agent, oiliness suspending agent or syrup;
The pharmaceutical dosage form that described snuffing is gone into is a nasal spray;
The solution that described parenteral pharmaceutical dosage form is an injection, aqueous suspension agent or oiliness suspending agent;
The pharmaceutical dosage form of described topical is cream, ointment, patch, spray or subcutaneous implant.
8, pharmaceutical composition as claimed in claim 7 is characterized in that: described tablet is slow releasing tablet or coated tablet.
9, pharmaceutical composition as claimed in claim 4 is characterized in that: the dosage form of described pharmaceutical composition is the preparation at the specific part slow release of intestinal.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910206250XA CN101669935B (en) | 2005-10-25 | 2005-10-25 | Drug combination containing prunetin and application thereof in drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910206250XA CN101669935B (en) | 2005-10-25 | 2005-10-25 | Drug combination containing prunetin and application thereof in drugs |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100310973A Division CN100546575C (en) | 2005-10-25 | 2005-10-25 | A kind of pharmaceutical composition that contains pratensein, prunusetin. and in pharmaceutically application |
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| Publication Number | Publication Date |
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| CN101669935A true CN101669935A (en) | 2010-03-17 |
| CN101669935B CN101669935B (en) | 2013-12-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104208058A (en) * | 2014-08-18 | 2014-12-17 | 周玉梅 | Application of sodium prunusetin-3'-sulfonate to prepare medicines for treating male infertility |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003075943A2 (en) * | 2002-03-06 | 2003-09-18 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising wogonin, isoliquiritigenin and/or coumestrol |
| CN1984648A (en) * | 2003-03-06 | 2007-06-20 | 医学研究和教育联合企业 | Botanical extract compositions and methods of use |
-
2005
- 2005-10-25 CN CN200910206250XA patent/CN101669935B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003075943A2 (en) * | 2002-03-06 | 2003-09-18 | The Medical Research And Education Trust | Botanical extract compositions with anti-cancer or phytoestrogenic activity comprising wogonin, isoliquiritigenin and/or coumestrol |
| CN1984648A (en) * | 2003-03-06 | 2007-06-20 | 医学研究和教育联合企业 | Botanical extract compositions and methods of use |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104208058A (en) * | 2014-08-18 | 2014-12-17 | 周玉梅 | Application of sodium prunusetin-3'-sulfonate to prepare medicines for treating male infertility |
| CN104208058B (en) * | 2014-08-18 | 2016-05-11 | 李健 | The application of prunetin-3 '-sodium sulfonate in the medicine of preparation treatment male sterility |
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| CN101669935B (en) | 2013-12-11 |
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